Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom

ABSTRACT

The invention relates to the film products and methods of their preparation that demonstrate a non-self-aggregating uniform heterogeneity. Desirably the films disintegrate in water and may be formed by a controlled drying process, or other process that maintains the required uniformity of the film.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/672,228, filed Aug. 8, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/945,181, filed Nov. 18, 2015, which is acontinuation of U.S. patent application Ser. No. 11/092,217, filed Mar.29, 2005, which is a continuation of U.S. patent application Ser. No.10/074,272, filed Feb. 14, 2002, now U.S. Pat. No. 7,425,292, whichclaims the benefit of U.S. Provisional Application No. 60/328,868, filedOct. 12, 2001, the contents all of which are incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to rapidly dissolving films and methods of theirpreparation. The films may also contain an active ingredient that isevenly distributed throughout the film. The even or uniform distributionis achieved by controlling one or more parameters, and particularly thedrying process that reduces aggregation or conglomeration of thecomponents in the film as it forms into a solid structure.

BACKGROUND OF THE RELATED TECHNOLOGY

Active ingredients such as drugs or pharmaceuticals, may be prepared ina tablet form to allow for accurate and consistent dosing. However, thisform of preparing and dispensing medications has many disadvantagesincluding that a large proportion of adjuvants that must be added toobtain a size able to be handled, that a larger medication form requiresadditional storage space, and that dispensing includes counting thetablets which has a tendency for inaccuracy. In addition, many persons,estimated to be as much as 28% of the population, have difficultyswallowing tablets. While tablets may be broken into smaller pieces oreven crushed as a means of overcoming swallowing difficulties, this isnot a suitable solution for many tablet or pill forms. For example,crushing or destroying the tablet or pill form to facilitate ingestion,alone or in admixture with food, may also destroy the controlled releaseproperties.

As an alternative to tablets and pills, films may be used to carryactive ingredients such as drugs, pharmaceuticals, and the like.However, historically films and the process of making drug deliverysystems therefrom have suffered from a number of unfavorablecharacteristics that have not allowed them to be used in practice.

Films that incorporate a pharmaceutically active ingredient aredisclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et al. (“Fuchs”).These films may be formed into a sheet, dried and then cut intoindividual doses. The Fuchs disclosure alleges the fabrication of auniform film, which includes the combination of water-soluble polymers,surfactants, flavors, sweeteners, plasticizers and drugs. Theseallegedly flexible films are disclosed as being useful for oral, topicalor enteral use. Examples of specific uses disclosed by Fuchs includesapplication of the films to mucosal membrane areas of the body,including the mouth, rectal, vaginal, nasal and ear areas.

Examination of films made in accordance with the process disclosed inFuchs, however, reveals that such films suffer from the aggregation orconglomeration of particles, i.e., self-aggregation, making theminherently non-uniform. This result can be attributed to Fuchs' processparameters, which although not disclosed likely include the use ofrelatively long drying times, thereby facilitating intermolecularattractive forces, convection forces, air flow and the like to form suchagglomeration.

The formation of agglomerates randomly distributes the film componentsand any active present as well. When large dosages are involved, a smallchange in the dimensions of the film would lead to a large difference inthe amount of active per film. If such films were to include low dosagesof active, it is possible that portions of the film may be substantiallydevoid of any active. Since sheets of film are usually cut into unitdoses, certain doses may therefore be devoid of or contain aninsufficient amount of active for the recommended treatment. Failure toachieve a high degree of accuracy with respect to the amount of activeingredient in the cut film can be harmful to the patient. For thisreason, dosage forms formed by processes such as Fuchs, would not likelymeet the stringent FDA standards relating to the variation of active indosage forms. Currently, by law, dosage forms may not vary more than 10%in the amount of active present. When applied to dosage units based onfilms, this virtually mandates that uniformity in the film be present.

The problems of self-aggregation leading to non-uniformity of a filmwere addressed in U.S. Pat. No. 4,849,246 to Schmidt (“Schmidt”).Schmidt specifically pointed out that the methods disclosed by Fuchs didnot provide a uniform film and recognized that that the creation of anon-uniform film necessarily prevents accurate dosing, which asdiscussed above is especially important in the pharmaceutical area.Schmidt abandoned the idea that a mono-layer film, such as described byFuchs, may provide an accurate dosage form and instead attempted tosolve this problem by forming a multi-layered film. Moreover, hisprocess is a multi-step process that adds expense and complexity and isnot practical for commercial use.

Other U.S. Patents directly addressed the problems of particleself-aggregation and non-uniformity inherent in conventional filmforming techniques. In one attempt to overcome non-uniformity, U.S. Pat.No. 5,629,003 to Horstmann et al. and U.S. Pat. No. 5,948,430 to Zerbeet al. incorporated additional ingredients, i.e. gel formers andpolyhydric alcohols respectively, to increase the viscosity of the filmprior to drying in an effort to reduce aggregation of the components inthe film. These methods have the disadvantage of requiring additionalcomponents, which translates to additional cost and manufacturing steps.Furthermore, both methods employ the use the conventional time-consumingdrying methods such as a high-temperature air-bath using a drying oven,drying tunnel, vacuum drier, or other such drying equipment. The longlength of drying time aids in promoting the aggregation of the activeand other adjuvant, notwithstanding the use of viscosity modifiers. Suchprocesses also run the risk of exposing the active, i.e., a drug, orvitamin C, or other components to prolonged exposure to moisture andelevated temperatures, which may render it ineffective or even harmful.

In addition to the concerns associated with degradation of an activeduring extended exposure to moisture, the conventional drying methodsthemselves are unable to provide uniform films. The length of heatexposure during conventional processing, often referred to as the “heathistory”, and the manner in which such heat is applied, have a directeffect on the formation and morphology of the resultant film product.Uniformity is particularly difficult to achieve via conventional dryingmethods where a relatively thicker film, which is well-suited for theincorporation of a drug active, is desired. Thicker uniform films aremore difficult to achieve because the surfaces of the film and the innerportions of the film do not experience the same external conditionssimultaneously during drying. Thus, observation of relatively thickfilms made from such conventional processing shows a non-uniformstructure caused by convection and intermolecular forces and requiresgreater than 10% moisture to remain flexible. The amount of freemoisture can often interfere over time with the drug leading to potencyissues and therefore inconsistency in the final product.

Conventional drying methods generally include the use of forced hot airusing a drying oven, drying tunnel, and the like. The difficulty inachieving a uniform film is directly related to the rheologicalproperties and the process of water evaporation in the film-formingcomposition. When the surface of an aqueous polymer solution iscontacted with a high temperature air current, such as a film-formingcomposition passing through a hot air oven, the surface water isimmediately evaporated forming a polymer film or skin on the surface.This seals the remainder of the aqueous film-forming composition beneaththe surface, forming a barrier through which the remaining water mustforce itself as it is evaporated in order to achieve a dried film. Asthe temperature outside the film continues to increase, water vaporpressure builds up under the surface of the film, stretching the surfaceof the film, and ultimately ripping the film surface open allowing thewater vapor to escape. As soon as the water vapor has escaped, thepolymer film surface reforms, and this process is repeated, until thefilm is completely dried. The result of the repeated destruction andreformation of the film surface is observed as a “ripple effect” whichproduces an uneven, and therefore non-uniform film. Frequently,depending on the polymer, a surface will seal so tightly that theremaining water is difficult to remove, leading to very long dryingtimes, higher temperatures, and higher energy costs.

Other factors, such as mixing techniques, also play a role in themanufacture of a pharmaceutical film suitable for commercialization andFederal approval. Air is generally trapped in the composition during themixing process, which can leave voids as the moisture evaporates duringthe drying stage. The results is non-uniformity in the final filmproduct.

Therefore, there is a need for methods and compositions for filmproducts, which use a minimal number of materials or components, andwhich provide a substantially non-self-aggregating uniform heterogeneitythroughout the area of the films. Desirably, such films are producedthrough a selection of a polymer or combination of polymers that willprovide a desired viscosity, a film-forming process such as reverse rollcoating, and a controlled, and desirably rapid, drying process whichserves to maintain the uniform distribution of non-self-aggregatedcomponents without the necessary addition of gel formers or polyhydricalcohols and the like which appear to be required in the products andfor the processes of prior patents, such as the aforementioned Horstmannand Zerbe patents.

SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a film and amethod of forming same which can be divided into equally sized dosageunits having substantially equal amounts of each compositional componentpresent. This advantage is particularly useful because it permits largearea films to be initially formed, and subsequently cut into individualdosage units without concern for whether each unit is compositionallyequal. For example, the films of the present invention have particularapplicability as pharmaceutical dosage delivery systems because eachdosage unit, e.g., each individual dosage film unit, will contain theproper amount of drug. Pharmaceutical film dosage forms to date have notbeen marketed largely due to the inability to achieve this result.

In a further aspect of the present invention, there is provided a filmproduct that is formed by combining a polymer and a polar solvent,forming the combination into a film, and drying the film in a controlledmanner, desirably by initially only applying heat to the bottom side ofthe film, in order to maintain a non-self-aggregating uniformheterogeneity. Desirably, during the initial bottom drying stage,substantially no convection currents, i.e. hot air currents, arepermitted to travel across the tops of the films. Once the visco-elasticproperties of the film are such that the film components are “locked” inplace and cannot move to cause non-uniformity, other methods of heatingmay then be employed. The polar solvent may be water, a polar organicsolvent, or a combination thereof. An active ingredient may be added tothe polymer and water combination prior to the drying step.Alternatively, or in addition to controlling the drying the film, thepolymer may be selected in order to provide a viscosity that maintainsthe non-self-aggregating uniform heterogeneity. Moreover, thecomposition desirably is mixed in a manner to minimize the incorporationof air into the mixture and is desirably deaerated, such as byconditioning at room temperature, vacuum treatment or the like, to allowtrapped air to escape prior to the drying process. This serves toeliminate bubble and void formation in the final film product, therebyfurther improving uniformity. Reverse roll is one particularly usefulcoating technique may also be used to form the film.

In another aspect of the invention, there is a process for preparing afilm with a substantially uniform distribution of components. Theprocess includes the steps of combining a polymer component and water toform a uniformly distributed matrix. This matrix is then formed into afilm and fed onto the top side of a substrate surface having top andbottom sides. Heat is applied to the bottom side of the substratesurface in order to dry the film. The matrix from which the film isformed may also include an active ingredient. Also, eitheralternatively, or in addition to the particular method used to dry thefilm, the polymer may be selected in order to provide a viscosity thatmaintains the non-self-aggregating uniform heterogeneity. Reverse rollcoating technique may also be used to form the film.

A further aspect of the present invention is a method of orallyadministering an active including the steps of:

(a) preparing a film by the steps of:

-   -   (i) combining a polymer, an active component, and water to form        a material with a non-self-aggregating uniform heterogeneity;    -   (ii) forming the material into a film; and    -   (iii) drying the film in a controlled manner to maintain the        non-self-aggregating uniform heterogeneity; and

(b) introducing the film to the oral cavity of a mammal.

An even further aspect of the present invention is method of introducingan active component to liquid including the steps of:

(a) preparing a film by the steps of:

-   -   (i) combining a polymer, an active component, and water to form        a material with a non-self-aggregating uniform heterogeneity;    -   (ii) forming the material into a film; and    -   (iii) drying the film in a controlled manner to maintain the        non-self-aggregating uniform heterogeneity; and

(b) placing the film into a liquid; and

(c) allowing the film to dissolve.

A still further aspect of the present invention provides a dosage formfor the administration of an active including:

-   -   (a) a first layer including a film formed by the steps of:        -   (i) combining a polymer, an active component, and water to            form a material with a non-self-aggregating uniform            heterogeneity;        -   (ii) forming said material into a film; and        -   (iii) drying said film in a controlled manner to maintain            said non-self-aggregating uniform heterogeneity; and    -   (b) a substantially non-water soluble second layer.

Another aspect of the present invention provides a method of preparing adosage form for the administration of an active including the steps of:

-   -   (a) combining a polymer, an active component, and water to form        a material with a non-self-aggregating uniform heterogeneity;    -   (b) forming the material into a film;    -   (c) applying the film to a substantially non-water soluble        support; and    -   (d) drying the film in a controlled manner to maintain the        non-self-aggregating uniform heterogeneity.

In still another aspect of the present invention there is providedanother method of administering an active including the steps of:

(a) preparing dosage form by the steps of:

-   -   (i) combining a polymer, an active component, and water to form        a material with a non-self-aggregating uniform heterogeneity;    -   (ii) forming the material into a film;    -   (iii) applying the film to a substantially non-water soluble        support; and    -   (iv) drying the film in a controlled manner to maintain the        non-self-aggregating uniform heterogeneity;

(b) removing the film from said support; and

(c) applying the film to the oral cavity of a mammal.

Another aspect of the invention provides a film product formed by thesteps of:

(a) combining a polymer and a liquid carrier to form a material with anon-self-aggregating uniform heterogeneity;

(b) forming said material into a film; and

(c) removing said liquid carrier, for example, by evaporative methods orby permitting volatilization to occur at selected temperatures, fromsaid film in a manner to maintain said non-self-aggregating uniformheterogeneity.

Also provided is a process for making a film having a substantiallyuniform distribution of components including:

(a) combining a polymer component and liquid carrier to form a matrixwith a uniform distribution of said components;

(b) forming a film from said matrix; and

(c) removing said liquid carrier, for example, by evaporative methods orby permitting volatilization to occur at selected temperatures, fromsaid film in a manner to maintain said uniform distribution.

A still further aspect of the present invention provides process formaking a film having a substantially uniform distribution of componentsincluding:

(a) combining a polymer component and a polar solvent to form a matrixwith a uniform distribution of said components, said polymer selected toprovide a viscosity sufficient to maintain said uniform distribution;and

(b) forming a film from said matrix.

The invention also includes films and a process for preparing filmshaving a substantially uniform distribution of components. The processincludes the steps of combining a polymer component and water to form auniformly distributed matrix. This matrix is then formed into a film andfed onto a substrate surface having top and bottom sides where thebottom side is in substantially uniform contact with a bottom dryingmedium, such as a water bath or heated air space controlled at atemperature sufficient to dry the film. Desirably, no external aircurrents or heat is applied directly to the exposed top surface of thefilm during the drying process until the film structure has solidifiedsufficiently to prevent flow, migration and intermolecular attractiveforces from creating aggregates or conglomerates. Desirably the heat iscontrollably conducted by the substrate surface to the film toeffectuate drying. The matrix from which the film is formed may alsoinclude an active ingredient. Also, either alternatively, or in additionto rapidly drying the film, the polymer may be selected in order toprovide a viscosity that maintains the non-self-aggregating uniformheterogeneity.

A pharmaceutical and/or cosmetic dosage form is also provided thatincludes a film having a uniformly dispersed composition including apolymer, a pharmaceutical and/or cosmetic active and a solvent, saidfilm being formed by depositing a wet film of said composition onto asubstrate surface and controllably drying the wet film from the sidecontacting the substrate to prevent self-aggregation and achievecompositional uniformity.

A still further aspect of the present invention includes apharmaceutical and/or cosmetic dosage form including a polymeric filmhaving no more than a 10% variance of a pharmaceutical and/or cosmeticactive per unit area.

The present invention also provides a pharmaceutical composition in theform of a film for external or topical administration, including acomposition having a uniformly distributed combination of a polymer, apolar solvent, and a pharmaceutical active, said composition in itsdried film form maintaining the uniform distribution of componentsthrough the application of controlled bottom drying of the film.

A pharmaceutical dispenser is also provided that includes individualunit dosage forms of the pharmaceutical compositions and films of thepresent invention. The dosage forms may be optionally stacked in adispenser or in a roll.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a side view of a package containing a unit dosage film ofthe present invention.

FIG. 2 shows a top view of two adjacently coupled packages containingindividual unit dosage forms of the present invention, separated by atearable perforation.

FIG. 3 shows a side view of the adjacently coupled packages of FIG. 2arranged in a stacked configuration.

FIG. 4 shows a perspective view of a dispenser for dispensing thepackaged unit dosage forms, dispenser containing the packaged unitdosage forms in a stacked configuration.

FIG. 5 is a schematic view of a roll of coupled unit dose packages ofthe present invention.

FIG. 6 is a schematic view of an apparatus suitable for preparation of apre-mix, addition of an active, and subsequent formation of the film.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention the term non-self-aggregatinguniform heterogeneity refers to the ability of the films of the presentinvention, which are formed from one or more components in addition to apolar solvent, to provide a substantially reduced occurrence of, i.e.little or no, aggregation or conglomeration of components within thefilm as is normally experienced when films are formed by conventionaldrying methods such as a high-temperature air-bath using a drying oven,drying tunnel, vacuum drier, or other such drying equipment. The termheterogeneity, as used in the present invention, includes films thatwill incorporate a single component, such as a polymer, as well ascombinations of components, such as a polymer and an active. Uniformheterogeneity includes the substantial absence of aggregates orconglomerates as is common in conventional mixing and heat dryingmethods used to form films.

Furthermore, the films of the present invention have a substantiallyuniform thickness, which is also not provided by the use of conventionaldrying methods used for drying water-based polymer systems. The absenceof a uniform thickness detrimentally affects uniformity of componentdistribution throughout the area of a given film.

The film products of the present invention are produced by a combinationof a properly selected polymer and a polar solvent, optionally includingan active ingredient as well as other fillers known in the art. Thesefilms provide a non-self-aggregating uniform heterogeneity of thecomponents within them by utilizing a selected casting or depositionmethod and a controlled drying process. Examples of controlled dryingprocesses include, but are not limited to, the use of the apparatusdisclosed in U.S. Pat. No. 4,631,837 to Magoon (“Magoon”), hereinincorporated by reference, as well as hot air impingement across thebottom substrate and bottom heating plates. Another drying technique forobtaining the films of the present invention is controlled radiationdrying in the absence of air currents, such as infrared and radiofrequency radiation (i.e. microwaves).

The objective of the drying process is to provide a method of drying thefilms that avoids complications, such as the noted “rippling” effect,that are associated with conventional drying methods and which initiallydry the upper surface of the film, trapping moisture inside. Inconventional oven drying methods, as the moisture trapped insidesubsequently evaporates, the top surface is altered by being ripped openand then reformed. These complications are avoided by the presentinvention, and a uniform film is provided by drying the bottom surfaceof the film first or otherwise preventing the formation of polymer filmformation (skin) on the top surface of the film prior to drying thedepth of the film. This may be achieved by applying heat to the bottomsurface of the film with substantially no top air flow, or alternativelyby the introduction of controlled microwaves to evaporate the water orother polar solvent within the film, again with substantially no top airflow. The humidity level of the area surrounding the top surface mayalso be appropriately adjusted to prevent premature closure or skinningof the polymer surface.

This manner of drying the films provides several advantages. Among theseare the faster drying times and a more uniform surface of the film, aswell as uniform distribution of components for any given area in thefilm. In addition, the faster drying time allows viscosity to quicklybuild within the film, further encouraging a uniform distribution ofcomponents and decrease in aggregation of components in the final filmproduct. Desirably, the drying of the film will occur within about tenminutes or fewer, or more desirably within about five minutes or fewer.

The present invention yields exceptionally uniform film products whenattention is paid to reducing the aggregation of the compositionalcomponents. By avoiding the introduction of and eliminating excessiveair in the mixing process, selecting polymers and solvents to provide acontrollable viscosity and by drying the film in a rapid manner from thebottom up, such films result.

The products and processes of the present invention rely on theinteraction among various steps of the production of the films in orderto provide films that substantially reduce the self-aggregation of thecomponents within the films. Specifically, these steps include theparticular method used to form the film, making the composition mixtureto prevent air bubble inclusions, controlling the viscosity of the filmforming composition and the method of drying the film. Moreparticularly, a greater viscosity of components in the mixture isparticularly useful when the active is not soluble in the selected polarsolvent in order to prevent the active from settling out. However, theviscosity must not be too great as to hinder or prevent the chosenmethod of casting, which desirably includes reverse roll coating due toits ability to provide a film of substantially consistent thickness.

While the viscosity and casting method are important in the first stepsof forming the film to promote uniformity, the method of drying is alsoimportant. Although the viscosity assists uniformity initially, a rapiddrying process ensures that the uniformity will be maintained until thefilm is dry. A number of techniques may be employed in the mixing stageto prevent bubble inclusions in the final film. To provide a compositionmixture with substantially no air bubble formation in the final product,anti-foaming or surface-tension reducing agents are employed.Additionally, the speed of the mixture is desirably controlled toprevent cavitation of the mixture in a manner which pulls air into themix. Finally, air bubble reduction can further be achieved by allowingthe mix to stand for a sufficient time for bubbles to escape prior todrying the film.

When the matrix is formed including the film-forming polymer and polarsolvent in addition to any additives and the active ingredient, this maybe done in a number of steps. For example, the ingredients may all beadded together or a pre-mix may be prepared. The advantage of a pre-mixis that all ingredients except for the active may be combined inadvance, with the active added just prior to formation of the film. Thisis especially important for actives that may degrade with prolongedexposure to water, air or another polar solvent.

FIG. 6 shows an apparatus 20 suitable for the preparation of a pre-mix,addition of an active and subsequent formation of a film. The pre-mix ormaster batch 22, which includes the film-forming polymer, polar solvent,and any other additives except a drug active is added to the masterbatch feed tank 24. Then a pre-determined amount of the master batch iscontrollably fed via a first metering pump 26 and control valve 28 toeither or both of the first and second mixers, 30, 31′. The requiredamount of the drug is added to the desired mixer through an opening ineach of the mixers, 32, 32′. After the drug has been blended with themaster batch pre-mix for a sufficient time to provide a uniform matrix,a specific amount of the uniform matrix is then fed to the pan 36through the second metering pumps, 34, 34′. The metering roller 38determines the thickness of the film 42 and applies it to theapplication roller. The film 42 is finally formed on the substrate 44and carried away via the support roller 46. The wet film is then driedusing controlled bottom drying, desirably in the absence of external aircurrents or heat on the top (exposed) surface of the film 48 asdescribed herein.

Monitoring and control of the thickness of the film also contributes tothe production of a uniform film by providing a film of uniformthickness. The thickness of the film may be monitored with gauges suchas Beta Gauges. A gauge may be coupled to another gauge at the end ofthe drying apparatus, i.e. drying oven or tunnel, to communicate throughfeedback loops to control and adjust the opening in the coatingapparatus, resulting in control of uniform film thickness.

The film products are generally formed by combining a properly selectedpolymer and polar solvent, as well as any active ingredient or filler asdesired. Desirably, the solvent content of the combination is at leastabout 30% by weight of the total combination. The matrix formed by thiscombination is formed into a film, desirably by roll coating, and thendried, desirably by a rapid and controlled drying process to maintainthe uniformity of the film, more specifically, a non-self-aggregatinguniform heterogeneity. The resulting film will desirably contain lessthan about 10% by weight solvent, more desirably less than about 8% byweight solvent, even more desirably less than about 6% by weight solventand most desirably less than about 2%. The solvent may be water, a polarorganic solvent including, but not limited to, ethanol, isopropanol,acetone, methylene chloride, or any combination thereof.

Film-Forming Polymers

The polymer may be water soluble, water insoluble, or a combination ofone or more either water soluble or water insoluble polymers. Thepolymer may include cellulose or a cellulose derivative. Specificexamples of useful water soluble polymers include, but are not limitedto, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose,polyvinyl alcohol, sodium aginate, polyethylene glycol, xanthan gum,tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl copolymers, starch, andcombinations thereof. Specific examples of useful water insolublepolymers include, but are not limited to, ethyl cellulose, hydroxypropylethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and combinations thereof.

Other polymers useful for incorporation into the films of the presentinvention include biodegradable polymers, copolymers, block polymers andcombinations thereof. Among the known useful polymers or polymer classeswhich meet the above criteria are: poly(glycolic acid) (PGA),poly(lactic acid) (PLA), polydioxanoes, polyoxalates, poly(α-esters),polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters),polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates,polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymersthereof. Additional useful polymers include, stereopolymers of L- andD-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid andsebacic acid, sebacic acid copolymers, copolymers of caprolactone,poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers,copolymers of polyurethane and (poly(lactic acid), copolymers ofpolyurethane and poly(lactic acid), copolymers of α-amino acids,copolymers of α-amino acids and caproic acid, copolymers of α-benzylglutamate and polyethylene glycol, copolymers of succinate andpoly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixturesthereof. Binary and ternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorband Biodel trademarks. The Medisorb materials are marketed by the DupontCompany of Wilmington, Del. and are generically identified as a“lactide/glycolide co-polymer” containing “propanoic acid,2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid.” Foursuch polymers include lactide/glycolide 100 L, believed to be 100%lactide having a melting point within the range of 338°-347° F.(170°-175° C.); lactide/glycolide 100 L, believed to be 100% glycolidehaving a melting point within the range of 437°-455° F. (225°-235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°-347° F. (170°-175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Although a variety of different polymers may be used, it is desired toselect polymers to provide a desired viscosity of the mixture prior todrying. For example, if the active or other components are not solublein the selected solvent, a polymer that will provide a greater viscosityis desired to assist in maintaining uniformity. On the other hand, ifthe components are soluble in the solvent, a polymer that provides alower viscosity may be preferred.

The polymer plays an important role in affecting the viscosity of thefilm. Viscosity is one property of a liquid that controls the stabilityof the active in an emulsion, a colloid or a suspension. Generally theviscosity of the matrix will vary from about 400 cps to about 100,000cps, preferably from about 800 cps to about 60,000 cps, and mostpreferably from about 1,000 cps to about 40,000 cps. Desirably, theviscosity of the film-forming matrix will rapidly increase uponinitiation of the drying process.

The viscosity may be adjusted based on the selected active depending onthe other components within the matrix. For example, if the component isnot soluble within the selected solvent, a proper viscosity may beselected to prevent the component from settling which would adverselyaffect the uniformity of the resulting film. The viscosity may beadjusted in different ways. To increase viscosity of the film matrix,the polymer may be chosen of a higher molecular weight or crosslinkersmay be added, such as salts of calcium, sodium and potassium. Theviscosity may also be adjusted by adjusting the temperature or by addinga viscosity increasing component. Components that will increase theviscosity or stabilize the emulsion/suspension include higher molecularweight polymers and polysaccharides and gums, which include withoutlimitation, alginate, carrageenan, hydroxypropyl methyl cellulose,locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gumand combinations thereof.

Controlled Release Films

The term “controlled release” is intended to mean the release of activeat a pre-selected or desired rate. This rate will vary depending uponthe application. Desirable rates include fast or immediate releaseprofiles as well as delayed, sustained or sequential release.Combinations of release patterns, such as initial spiked releasefollowed by lower levels of sustained release of active arecontemplated.

The polymers that are chosen for the films of the present invention mayalso be chosen to allow for controlled disintegration of the active.This may be achieved by providing a substantially water insoluble filmthat incorporates an active that will be released from the film overtime. This may be accomplished by incorporating a variety of differentsoluble or insoluble polymers and may also include biodegradablepolymers in combination. Alternatively, coated controlled release activeparticles may be incorporated into a readily soluble film matrix toachieve the controlled release property of the active inside thedigestive system upon consumption.

Films that provide a controlled release of the active are particularlyuseful for buccal, gingival, and sublingual applications.

The convenience of administering a single dose of a medication whichreleases active ingredients in a controlled fashion over an extendedperiod of time as opposed to the administration of a number of singledoses at regular intervals has long been recognized in thepharmaceutical arts. The advantage to the patient and clinician inhaving consistent and uniform blood levels of medication over anextended period of time are likewise recognized. The advantages of avariety of sustained release dosage forms are well known. However, thepreparation of a film that provides the controlled release of an activehas advantages in addition to those well-known for controlled releasetablets. For example, thin films are difficult to inadvertently aspirateand provide an increased patient compliance because they need not beswallowed like a tablet. Moreover, certain embodiments of the inventivefilms are designed to adhere to the buccal cavity and tongue, where theycontrollably dissolve. Furthermore, thin films may not be crushed in themanner of controlled release tablets which is a problem leading to abuseof drugs such as Oxycontin.

The actives employed in the present invention may be incorporated intothe film compositions of the present invention in a controlled releaseform. For example, particles of drug may be coated with polymers such asethyl cellulose or polymethacrylate, commercially available under brandnames such as Aquacoat ECD and Eudragit E-100, respectively. Solutionsof drug may also be absorbed on such polymer materials and incorporatedinto the inventive film compositions. Other components such as fats andwaxes, as well as sweeteners and/or flavors may also be employed in suchcontrolled release compositions.

Actives

When an active is introduced to the film, the amount of active per unitarea is determined by the uniform distribution of the film. For example,when the films are cut into individual dosage forms, the amount of theactive in the dosage form can be known with a great deal of accuracy.This is achieved because the amount of the active in a given area issubstantially identical to the amount of active in an area of the samedimensions in another part of the film. The accuracy in dosage isparticularly advantageous when the active is a medicament, i.e. a drug.

The active components that may be incorporated into the films of thepresent invention include, without limitation pharmaceutical andcosmetic actives, drugs, medicaments, mouthwash components, flavors,fragrances, enzymes, preservatives, sweetening agents, colorants,spices, vitamins and combinations thereof.

A wide variety of medicaments and pharmaceutical compositions may beincluded in the dosage forms of the present invention. Examples ofuseful drugs include ace-inhibitors, antianginal drugs,anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics,anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents,anti-diarrhea preparations, antidotes, anti-histamines,anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents,anti-manics, anti-nauseants, anti-stroke agents, anti-thyroidpreparations, anti-tumor drugs, anti-viral agents, acne drugs,alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs,anti-viral drugs, anabolic preparations, systemic and non-systemicanti-infective agents, anti-neoplastics, anti-parkinsonian agents,anti-rheumatic agents, appetite stimulants, biological responsemodifiers, blood modifiers, bone metabolism regulators, cardiovascularagents, central nervous system stimulates, cholinesterase inhibitors,contraceptives, decongestants, dietary supplements, dopamine receptoragonists, endometriosis management agents, enzymes, erectile dysfunctiontherapies, fertility agents, gastrointestinal agents, homeopathicremedies, hormones, hypercalcemia and hypocalcemia management agents,immunomodulators, immunosuppressives, migraine preparations, motionsickness treatments, muscle relaxants, obesity management agents,osteoporosis preparations, oxytocics, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sedatives, smoking cessation aids, sympatholytics,tremor preparations, urinary tract agents, vasodilators, laxatives,antacids, ion exchange resins, anti-pyretics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, psycho-tropics, stimulants, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thromboticdrugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid andanti-thyroid preparations, diuretics, anti-spasmodics, terine relaxants,anti-obesity drugs, erythropoietic drugs, anti-asthmatics, coughsuppressants, mucolytics, DNA and genetic modifying drugs, andcombinations thereof.

Examples of medicating active ingredients contemplated for use in thepresent invention include antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide Moreover, antacids can be used in combination withH₂-antagonists.

Analgesics include opiates and opiate derivatives, such as Oxycontin,ibuprofen, aspirin, acetaminophen, and combinations thereof that mayoptionally include caffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include anti-diarrheals such as immodium AD,anti-histamines, anti-tussives, decongestants, vitamins, and breathfresheners. Also contemplated for use herein are anxiolytics such asXanax; anti-psychotics such as clozaril and Haldol; non-steroidalanti-inflammatories (NSAID's) such as Voltaren and Lodine,anti-histamines such as Claritin, Hismanal, Relafen, and Tavist;anti-emetics such as Kytril and Cesamet; bronchodilators such asBentolin, Proventil; anti-depressants such as Prozac, Zoloft, and Paxil;anti-migraines such as Imigra, ACE-inhibitors such as Vasotec, Capotenand Zestril; anti-Alzheimer's agents, such as Nicergoline; andCa^(H)-antagonists such as Procardia, Adalat, and Calan.

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium carbonate, calcium phosphate, citrate ion (acidor salt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono-ordibasic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts.

An anti-oxidant may also be added to the film to prevent the degradationof an active, especially where the active is photosensitive.

Cosmetic active agents may include breath freshening compounds likementhol, other flavors or fragrances, especially those used for oralhygiene, as well as actives used in dental and oral cleansing such asquaternary ammonium bases. The effect of flavors may be enhanced usingflavor enhancers like tartaric acid, citric acid, vanillin, or the like.

Also color additives can be used in preparing the films. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

The flavorings may be added to provide a hot or cold flavored drink orsoup. These flavorings include, without limitation, tea and soupflavorings such as beef and chicken.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof; saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,xylitol, and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

When the active is combined with the polymer in the solvent, the type ofmatrix that is formed depends on the solubilities of the active and thepolymer. If the active and/or polymer are soluble in the selectedsolvent, this may form a solution. However, if the components are notsoluble, the matrix may be classified as an emulsion, a colloid, or asuspension.

Dosages

The film products of the present invention are capable of accommodatinga wide range of amounts of the active ingredient. The films are capableof providing an accurate dosage amount (determined by the size of thefilm and concentration of the active in the original polymer/watercombination) regardless of whether the required dosage is high orextremely low. Therefore, depending on the type of active orpharmaceutical composition that is incorporated into the film, theactive amount may be as high as about 300 mg, desirably up to about 150mg or as low as the microgram range, or any amount therebetween.

The film products and methods of the present invention are well suitedfor high potency, low dosage drugs. This is accomplished through thehigh degree of uniformity of the films. Therefore, low dosage drugs,particularly more potent racemic mixtures of actives are desirable.

Optional Components

A variety of other components and fillers may also be added to the filmsof the present invention. These may include, without limitation,surfactants; plasticizers which assist in compatibilizing the componentswithin the mixture; polyalcohols; anti-foaming agents, such assilicone-containing compounds, which promote a smoother film surface byreleasing oxygen from the film; and thermo-setting gels such as pectin,carageenan, and gelatin, which help in maintaining the dispersion ofcomponents.

The variety of additives that can be incorporated into the inventivecompositions may provide a variety of different functions. Examples ofclasses of additives include excipients, lubricants, buffering agents,stabilizers, blowing agents, pigments, coloring agents, fillers, bulkingagents, sweetening agents, flavoring agents, fragrances, releasemodifiers, adjuvants, plasticizers, flow accelerators, mold releaseagents, polyols, granulating agents, diluents, binders, buffers,absorbents, glidants, adhesives, anti-adherents, acidulants, softeners,resins, demulcents, solvents, surfactants, emulsifiers, elastomers andmixtures thereof. These additives may be added with the activeingredient(s).

Useful additives include, for example, gelatin, vegetable proteins suchas sunflower protein, soybean proteins, cotton seed proteins, peanutproteins, grape seed proteins, whey proteins, whey protein isolates,blood proteins, egg proteins, acrylated proteins, water-solublepolysaccharides such as alginates, carrageenans, guar gum, agar-agar,xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gumkaraya, gum tragancanth), pectin, water-soluble derivatives ofcellulose: alkylcelluloses hydroxyalkylcelluloses andhydroxyalkylalkylcelluloses, such as methylcelulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose,hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcelluloseesters such as cellulose acetate phthalate (CAP),hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses,carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such ascarboxymethylcellulose and their alkali metal salts; water-solublesynthetic polymers such as polyacrylic acids and polyacrylic acidesters, polymethacrylic acids and polymethacrylic acid esters,polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP),polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, andpolycrotonic acids; also suitable are phthalated gelatin, gelatinsuccinate, crosslinked gelatin, shellac, water soluble chemicalderivatives of starch, cationically modified acrylates and methacrylatespossessing, for example, a tertiary or quaternary amino group, such asthe diethylaminoethyl group, which may be quaternized if desired; andother similar polymers.

Such extenders may optionally be added in any desired amount desirablywithin the range of up to about 80%, desirably about 3% to 50% and moredesirably within the range of 3% to 20% based on the weight of allcomponents.

Further additives may be inorganic fillers, such as the oxides ofmagnesium aluminum, silicon, titanium, etc. desirably in a concentrationrange of about 0.02% to about 3% by weight and desirably about 0.02% toabout 1% based on the weight of all components.

Further examples of additives are plasticizers which includepolyalkylene oxides, such as polyethylene glycols, polypropyleneglycols, polyethylene-propylene glycols, organic plasticizers with lowmolecular weights, such as glycerol, glycerol monoacetate, diacetate ortriacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol,sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributylcitrate, and the like, added in concentrations ranging from about 0.5%to about 30%, and desirably ranging from about 0.5% to about 20% basedon the weight of the polymer.

There may further be added compounds to improve the flow properties ofthe starch material such as animal or vegetable fats, desirably in theirhydrogenated form, especially those which are solid at room temperature.These fats desirably have a melting point of 50° C. or higher. Preferredare tri-glycerides with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀- and C22-fattyacids. These fats can be added alone without adding extenders orplasticizers and can be advantageously added alone or together withmono- and/or di-glycerides or phosphatides, especially lecithin. Themono- and di-glycerides are desirably derived from the types of fatsdescribed above, i.e. with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀- and C₂₂-fattyacids.

The total amounts used of the fats, mono-, di-glycerides and/orlecithins are up to about 5% and preferably within the range of about0.5% to about 2% by weight of the total composition

It is further useful to add silicon dioxide, calcium silicate, ortitanium dioxide in a concentration of about 0.02% to about 1% by weightof the total composition. These compounds act as texturizing agents.

These additives are to be used in amounts sufficient to achieve theirintended purpose. Generally, the combination of certain of theseadditives will alter the overall release profile of the activeingredient and can be used to modify, i.e. impede or accelerate therelease.

Lecithin is one surface active agent for use in the present invention.Lecithin can be included in the feedstock in an amount of from about0.25% to about 2.00% by weight. Other surface active agents, i.e.surfactants, include, but are not limited to, cetyl alcohol, sodiumlauryl sulfate, the Spans™ and Tweens™ which are commercially availablefrom ICI Americas, Inc. Carbowax™ is yet another modifier which is veryuseful in the present invention. Tweens™ or combinations of surfaceactive agents may be used to achieve the desired HLB.

As additional modifiers which enhance the procedure and product of thepresent invention are identified, Applicants intend to include all suchadditional modifiers within the scope of the invention claimed herein.

Other ingredients include binders which contribute to the ease offormation and general quality of the films. Non-limiting examples ofbinders include starches, pregelatinize starches, gelatin,polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone, andpolyvinylalcohols.

Forming the Film

The films of the present invention must be formed into a sheet prior todrying. After the desired components are combined to form amulti-component matrix, including the polymer, water, and an active orother components as desired, the combination is formed into a sheet orfilm, by any method known in the art such as extrusion, coating,spreading, casting or drawing the multi-component matrix. If amulti-layered film is desired, this may be accomplished by co-extrudingmore than one combination of components which may be of the same ordifferent composition. A multi-layered film may also be achieved bycoating, spreading, or casting a combination onto an already formed filmlayer.

Although a variety of different film-forming techniques may be used, itis desirable to select a method that will provide a flexible film, suchas reverse roll coating. The flexibility of the film allows for thesheets of film to be rolled and transported for storage or prior tobeing cut into individual dosage forms. Desirably, the films will alsobe self-supporting or in other words able to maintain their integrityand structure in the absence of a separate support. Furthermore, thefilms of the present invention may be selected of materials that areedible or ingestible.

Coating or casting methods are particularly useful for the purpose offorming the films of the present invention. Specific examples includereverse roll coating, gravure coating, immersion or dip coating,metering rod or meyer bar coating, slot die or extrusion coating, gap orknife over roll coating, air knife coating, curtain coating, orcombinations thereof, especially when a multi-layered film is desired.

Roll coating, or more specifically reverse roll coating, is particularlydesired when forming films in accordance with the present invention.This procedure provides excellent control and uniformity of theresulting films, which is desired in the present invention. In thisprocedure, the coating material is measured onto the applicator rollerby the precision setting of the gap between the upper metering rollerand the application roller below it. The coating is transferred from theapplication roller to the substrate as it passes around the supportroller adjacent to the application roller. Both three roll and four rollprocesses are common.

The gravure coating process relies on an engraved roller running in acoating bath, which fills the engraved dots or lines of the roller withthe coating material. The excess coating on the roller is wiped off by adoctor blade and the coating is then deposited onto the substrate as itpasses between the engraved roller and a pressure roller.

Offset Gravure is common, where the coating is deposited on anintermediate roller before transfer to the substrate.

In the simple process of immersion or dip coating, the substrate isdipped into a bath of the coating, which is normally of a low viscosityto enable the coating to run back into the bath as the substrateemerges.

In the metering rod coating process, an excess of the coating isdeposited onto the substrate as it passes over the bath roller. Thewire-wound metering rod, sometimes known as a Meyer Bar, allows thedesired quantity of the coating to remain on the substrate. The quantityis determined by the diameter of the wire used on the rod.

In the slot die process, the coating is squeezed out by gravity or underpressure through a slot and onto the substrate. If the coating is 100%solids, the process is termed “Extrusion” and in this case, the linespeed is frequently much faster than the speed of the extrusion. Thisenables coatings to be considerably thinner than the width of the slot.

The gap or knife over roll process relies on a coating being applied tothe substrate which then passes through a “gap” between a “knife” and asupport roller. As the coating and substrate pass through, the excess isscraped off.

Air knife coating is where the coating is applied to the substrate andthe excess is “blown off” by a powerful jet from the air knife. Thisprocedure is useful for aqueous coatings.

In the curtain coating process, a bath with a slot in the base allows acontinuous curtain of the coating to fall into the gap between twoconveyors. The object to be coated is passed along the conveyor at acontrolled speed and so receives the coating on its upper face.

Drying the Film

The drying step can also be a contributing factor with regard tomaintaining the uniformity of the film composition. A controlled dryingprocess is particularly important when, in the absence of a viscosityincreasing composition or a composition in which the viscosity iscontrolled, for example by the selection of the polymer, the componentswithin the film may have an increased tendency to aggregate orconglomerate. An alternative method of forming a film with an accuratedosage, that would not necessitate the controlled drying process, wouldbe to cast the films on a predetermined well. With this method, althoughthe components may aggregate, this will not result in the migration ofthe active to an adjacent dosage form, since each well may define thedosage unit per se.

When a controlled or rapid drying process is desired, this may bethrough a variety of methods. A variety of methods may be used includingthose that require the application of heat. The liquid carriers areremoved from the film in a manner such that the uniformity, or morespecifically, the non-self-aggregating uniform heterogeneity, that isobtained in the wet film is maintained.

Desirably, the film is dried from the bottom of the film to the top ofthe film. Substantially no air flow is present across the top of thefilm during its initial setting period, during which a solid,visco-elastic structure is formed. This can take place within the firstfew minutes, e.g. about the first 0.5 to about 4.0 minutes of the dryingprocess. Controlling the drying in this manner, prevents the destructionand reformation of the film's top surface, which results fromconventional drying methods. This is accomplished by forming the filmand placing it on the top side of a surface having top and bottom sides.Then, heat is initially applied to the bottom side of the film toprovide the necessary energy to evaporate or otherwise remove the liquidcarrier. The films dried in this manner dry more quickly and evenly ascompared to air-dried films, or those dried by conventional dryingmeans. In contrast to an air-dried film that dries first at the top andedges, the films dried by applying heat to the bottom dry simultaneouslyat the center as well as at the edges. This also prevents settling ofingredients that occurs with films dried by conventional means.

The temperature at which the films are dried is about 100° C. or less,desirably about 90° C. or less, and most desirably about 80° C. or less.

Another method of controlling the drying process, which may be usedalone or in combination with other controlled methods as disclosed aboveincludes controlling and modifying the humidity within the dryingapparatus where the film is being dried. In this manner, the prematuredrying of the top surface of the film is avoided.

A specific example of an appropriate drying method is that disclosed byMagoon. Magoon is specifically directed toward a method of drying fruitpulp. However, the present inventors have adapted this process towardthe preparation of thin films.

The method and apparatus of Magoon are based on an interesting propertyof water. Although water transmits energy by conduction and convectionboth within and to its surroundings, water only radiates energy withinand to water. Therefore, the apparatus of Magoon includes a surface ontowhich the fruit pulp is placed that is transparent to infraredradiation. The underside of the surface is in contact with a temperaturecontrolled water bath. The water bath temperature is desirablycontrolled at a temperature slightly below the boiling temperature ofwater. When the wet fruit pulp is placed on the surface of theapparatus, this creates a “refractance window.” This means that infraredenergy is permitted to radiate through the surface only to the area onthe surface occupied by the fruit pulp, and only until the fruit pulp isdry. The apparatus of Magoon provides the films of the present inventionwith an efficient drying time reducing the instance of aggregation ofthe components of the film.

The films may initially have a thickness of about 500 μm to about 1,500μm, or about 20 mils to about 60 mils, and when dried have a thicknessfrom about 3 μm to about 250 μm, or about 0.1 mils to about 10 mils.Desirably, the dried films will have a thickness of about 2 mils toabout 8 mils, and more desirably, from about 3 mils to about 6 mils.

Uses of Thin Films

The thin films of the present invention are well suited for many uses.The high degree of uniformity of the components of the film makes themparticularly well suited for incorporating pharmaceuticals. Furthermore,the polymers used in construction of the films may be chosen to allowfor a range of disintegration times for the films. A variation orextension in the time over which a film will disintegrate may achievecontrol over the rate that the active is released, which may allow for asustained release delivery system. In addition, the films may be usedfor the administration of an active to any of several body surfaces,especially those including mucous membranes, such as oral, anal,vaginal, ophthalmological, the surface of a wound, either on a skinsurface or within a body such as during surgery, and similar surfaces.

The films may be used to orally administer an active. This isaccomplished by preparing the films as described above and introducingthem to the oral cavity of a mammal. This film may be prepared andadhered to a second or support layer from which it is removed prior touse, i.e. introduction to the oral cavity. An adhesive may be used toattach the film to the support or backing material which may be any ofthose known in the art, and is preferably not water soluble. If anadhesive is used, it will desirably be a food grade adhesive that isingestible and does not alter the properties of the active. Mucoadhesivecompositions are particularly useful.

The films may be applied to the tongue of the mammal. When this isdesired, a specific film shape, corresponding to the shape of the tonguemay be preferred. Therefore the film may be cut to a shape where theside of the film corresponding to the back of the tongue will be longerthan the side corresponding to the front of the tongue. Specifically,the desired shape may be that of a triangle or trapezoid. Desirably, thefilm will adhere to the oral cavity preventing it from being ejectedfrom the oral cavity and permitting more of the active to be introducedto the oral cavity as the film dissolves.

Another use for the films of the present invention takes advantage ofthe films' tendency to dissolve quickly when introduce to a liquid. Anactive may be introduced to a liquid by preparing a film in accordancewith the present invention, introducing it to a liquid, and allowing itto dissolve. This may be used either to prepare a liquid dosage form ofan active, or to flavor a beverage.

The films of the present invention are desirably packaged in sealed, airand moisture resistant packages to protect the active from exposureoxidation, hydrolysis, volatilization and interaction with theenvironment. Referring to FIG. 1, a packaged pharmaceutical dosage unit10, includes each film 12 individually wrapped in a pouch or betweenfoil and/or plastic laminate sheets. The pouches 10, 10′ can be linkedtogether with tearable or perforated joints 16 and packaged in a roll asin FIG. 5 or stacked as shown in FIG. 3 and sold in a dispenser 18 asshown in FIG. 4. The dispenser may contain a full supply of themedication typically prescribed for the intended therapy, but due to thethinness of the film and package, is smaller and more convenient thantraditional bottles used for tablets, capsules and liquids. Moreover,the films of the present invention dissolve instantly upon contact withsaliva or mucosal membrane areas, eliminating the need to wash the dosedown with water.

Desirably, a series of such unit doses are packaged together inaccordance with the prescribed regimen or treatment, e.g., a 10-90 daysupply, depending on the particular therapy. The individual films can bepackaged on a backing and peeled off for use.

The features and advantages of the present invention are more fullyshown by the following examples which are provided for purposes ofillustration, and are not to be construed as limiting the invention inany way.

EXAMPLES

Water soluble thin film compositions of the present invention areprepared using the amounts described in Table 1.

TABLE 1 Weight (g) Ingredient A B C D E F G H I Hydroxypropylmethyl 1.761.63 32.00 3.67 32.00 cellulose Peppermint oil 0.90 1.0 1.05 8.0 2.67Sweetener 0.15 0.15 0.22 0.10 4.6 1.53 0.15 Polyvinylpyrrolidone 0.941.05 7.0 2.33 Tween 80¹ 0.5 0.5 2.0 0.65 11.80 1.35 0.5 11.80Simethicone² 0.2 0.2 0.15 0.30 1.80 0.21 0.2 1.80 Listerine³ 83.35 83.35Methylcellulose 6.0 Cornstarch⁴ 1.75 Agar 1.25 Water 42.24 93.63 39.22768.00 280.0 88.24 768.0 Loratadine⁵ 19.2 19.2 Pullulan⁶ 6.0 Ibuprofen38.4 ¹Available from ICI Americas ²Available from OSI ³Available fromPfizer, Inc. including thymol (0.064%), eucalyptol (0.092%), methylsalicylate (0.060%), menthol (0.042%), water (up to 72.8%), alcohol(26.9%), benzoic acid, poloxamer 407, sodium benzoate, and caramel color⁴Available from Grain Processing Corporation as Pure Cote B792⁵Available from Schering Corporation as Claritin ⁶Available fromHayashibara Biochemical Laboratories, Inc., Japan

The ingredients of inventive compositions A-I were combined by mixinguntil a uniform mixture was achieved. The compositions were then formedinto a film by reverse roll coating. These films were then dried on thetop side of an infrared transparent surface, the bottom side of whichwas in contact with a heated water bath at approximately 99° C. Noexternal thermal air currents were present above the film. The filmswere dried to less than about 6% by weight water in about 4 to 6minutes. The films were flexible, self-supporting and provided a uniformdistribution of the components within the film.

The uniform distribution of the components within the film was apparentby examination by either the naked eye or under slight magnification. Byviewing the films it was apparent that they were substantially free ofaggregation, i.e. the carrier and the actives remained substantially inplace and did not move substantially from one portion of the film toanother. Therefore, there was substantially no disparity among theamount of active found in any portion of the film.

Uniformity was also measured by first cutting the film into individualdosage forms. Twenty-five dosage forms of substantially identical sizewere cut from the film of inventive composition (E) above from randomlocations throughout the film. Then eight of these dosage forms wererandomly selected and additively weighed. The additive weights of eightrandomly selected dosage forms, are as shown in Table 2 below:

TABLE 2 Additive Weight (g) Sample Trial 1 Trial 2 1 0.04 0.04 2 0.080.08 3 0.12 0.12 4 0.16 0.16 5 0.20 0.20 6 0.24 0.24 7 0.28 0.28 8 0.320.32

The individual dosages were consistently 0.04 gm, which shows that thedistribution of the components within the film was consistent anduniform. This is based on the simple principal that each component has aunique density. Therefore, when the components of different densitiesare combined in a uniform manner in a film, as in the present invention,individual dosages forms from the same film of substantially equaldimensions, will contain the same mass.

An alternative method of determining the uniformity of the active is tocut the film into individual doses. The individual doses may then bedissolved and tested for the amount of active in films of particularsize. This demonstrates that films of substantially similar size cutfrom different locations on the same film contain substantially the sameamount of active.

When the films formed from inventive compositions A-H are placed on thetongue, they rapidly dissolve, releasing the active ingredient.Similarly, when they are placed in water, the films rapidly dissolvewhich provides a flavored drink when the active is chosen to be aflavoring.

Thin films that have a controlled degradation time and includecombinations of water soluble and water insoluble polymers and watersoluble films that allow controlled release of an active are preparedusing approximately the amounts described in Table 3.

TABLE 3 Weight (g) Ingredient J K L Hydroxypropylmethyl cellulose 1.01.0 Tween 80¹ 0.7 0.7 0.7 Water 5.0 Aquacoat ECD² 17.0 17.0 17.5Peppermint oil 1.0 0.4 1.1 ¹Available from ICI Americas ²A 30% by weightaqueous dispersion of ethyl cellulose available from FMC

The components of inventive compositions J-L were combined and formedinto films using the methods for preparing inventive compositions A-Iabove. These films were also flexible, self-supporting and provided auniform distribution of active which permits accuracy in dosing.

The uniformity of the films prepared from inventive compositions J-L mayalso be tested by either visual means measuring the weights ofindividual dosage films, or by dissolving the films and testing for theamount of active as described above.

An alternative method of preparing films which provides an accuratedosing may be used for any of inventive compositions A-I. The methodbegins with first combining the ingredients with mixing. The combinationof ingredients is then divided among individual wells or molds. In sucha method, aggregation of the components during drying is prevented bythe individual wells.

TABLE 4 Weight % Ingredient M N O 5% Methylcellulose Solution¹ 73.2244.22 74.22 Raspberry Flavor 3.28 3.28 3.28 Sweetener Blends 1.07 1.071.07 Tween-80² 2.47 2.47 2.47 Polyvinylpyrrolidone 3.30 3.30 3.30Ethanol 95% 8.24 8.24 8.24 Propylene Glycol 1.65 1.65 1.65 CalciumCarbonate 4.12 4.12 4.12 Cornstarch³ 1.65 1.65 1.65 Red Dye⁴ 1.00 CornSyrup⁵ 30.00 ¹Available from Dow Chemical Co. as Methocel K35 ²Availablefrom ICI Americas ³Available from Grain Processing Corporation as PureCote B792 ⁴Available from McCormick ⁵Available from Bestfoods, Inc. asKaro Syrup

The ingredients in the above Table 4 were combined and formed into afilm by casting the combination of ingredients onto the glass surfaceand applying heat to the bottom side of the glass. This providedinventive compositions M-O.

The film of composition M was examined both prior to and after dryingfor variations in the shading provided by the red dye. The film wasexamined both under sunlight and by incandescent bulb light. Novariations in shade or intensity of color were observed.

Further testing of the films of composition M included testing ofabsorption which is directly related to concentration. The film was cutinto segments each measuring 1.0 in. by 0.75 in., which wereconsecutively assigned numbers. Approximately 40 mg of the scrapmaterial from which the segments were cut was dissolved in about 10 mlof distilled water and then quantitatively transferred to a 25 mlvolumetric flask and brought to volume. The solution was centrifuged andscanned at 3nm intervals from 203-1200 nm. The frequency of maximumabsorption was found to be 530 nm. The solution was then re-centrifugedat a higher RPM (for the same length of time) and re-scanned, whichdemonstrated no change in the % transmission or frequency.

Each of the segments were weighed to 0.1 mg and then dissolved in 10 mldistilled water and transferred quantitatively to a 25 ml volumetricflask and brought to volume with distilled water. Each segment solutionwas then centrifuged as above, and then scanned, at first from 203-1200nm and later from only 500 nm to 550 nm at a 1 nm scanning speed. Thevalue recorded was the % transmission at the lowest wave length, whichwas most frequently 530 nm.

The absorption values are shown in Table 5 below:

TABLE 5 Segment mg/ % A 1-2 1.717 3-4 1.700 5-6 1.774 7* 1.701  9-101.721 11-12 1.729 13-14 1.725 15-16 1.713 *segment 8 was lost

The overall average absorption was 1.724. Of the 15 segments tested, thedifference between the highest and lowest values was 0.073 units, or 4%based on the average. This shows excellent control over the uniformityof the dye within the composition because the absorption is directlyproportional to the concentration of the dye within each segment.

The film of inventive composition N provided a very flexible film. Thisfilm was able to be stretched and exhibited a very high tensilestrength.

After forming the film of inventive composition O, the film was removedfrom the glass by very rapidly stripping the length of the glass with arazor. This provided very tightly wound “toothpick-like” dosage forms.Each dosage form consistently weighed 0.02 g. This demonstrates theuniformity of the dosage forms as well as the superior self-supportingproperties of the films.

TABLE 6 Weight (g) Ingredient P Q R S T U V W Hydroxypro- 320 320 320320 320 320 345 345 pylmethyl cellulose Water 1440 1440 1440 1440 1440999 999 Sweetener 60 60 45 Mint Flavor 80 80 Propylene 50 50 50 100 100100 100 69.3 Glycol Xanthan 22 11 11.23 10 10 10 6.9 Water/ 1440Ethanol(60/ 40) Orange 42 Flavor

TABLE 7 *1 *2 Film *1 Top Bottom *2 Top Bottom Film Coater Thickness v v*1 T v v *2 T Weight Speed % (Micron) (m/sec) (m/sec) (° C.) (m/sec)(m/sec) (° C.) (g) m/min Moisture P1 100 0 22 75 0 23 60 109 5 >20 P2350 0 22 75 0 23 60 n/a 5 >20 P3 350 0 40 75 0 40 60 161 3 >20 P4 350 040 75 0 40 75 191 3 >20 P5 350 10 40 75 10 40 75 253 3 >20 Q 350 0 40 7510 40 75 n/a 3 >20 R 350 0 40 85 10 0 85 2.5 >20 S1 250 0 40 100 0 40 90163 1.5 <5 S2 300 0 40 100 0 40 90 193 1.5 <5 S3 350 0 40 100 0 40 90225 1.5 <5 T1 250 0 40 100 0 40 90 64 1.5 <5 T2 350 0 40 100 0 40 90 831.5 <5 U1 300 0 40 100 0 40 90 208 1.5 20 U2 250 0 40 100 0 40 90 1771.5 20 U3 300 0 40 100 0 40 90 212 1.3 20 V1 300 0 40 100 0 40 90 2371.3 20 V2 300 0 40 100 0 40 100 242 1.3 20 V3 300 0 40 100 0 40 100 2211 6 W1 300 0 40 93 0 40 90 220 1.3 5 W2 250 0 40 90 0 40 90 199 1.3 5 W3200 0 40 90 0 40 90 169 1.3 5 *1 First Heater Section (3 m) *2 SecondHeater Section (3 m)

Compositions P-W were prepared to demonstrate the interaction amongvarious conditions in production of films as they relate to the presentinvention. The ingredients in the above Table 6 were combined and formedinto a film using the process parameters listed in Table 7 above,prepared in a 6 m drying tunnel designed to incorporate bottom drying ofthe films. Each of the examples shows the effect of different ingredientformulations and processing techniques on the resultant film products.

In Table 7, each of the process parameters contributes to differentproperties of the films. Film thickness refers to the distance betweenthe blade and the roller in the reverse roll coating apparatus. Bottomvelocity and top velocity refer to the speed of air current on thebottom and top sides of the film, respectively. The film weight is ameasure of the weight of a circular section of the substrate and thefilm of 100 cm².

Compositions P-R show the effects of visco-elastic properties on theability to coat the film composition mixture onto the substrate for filmformation. Composition P displayed a stringy elastic property. The wetfilm would not stay level, the coating was uneven, and the film did notdry. In Composition Q, substantially the same formulation as P was usedhowever the xanthan was not included. This product coated the substratebut would not stay level due to the change in the visco-elasticproperties of the wet foam. Composition R was prepared usingsubstantially the same formulation, but incorporated one-half of theamount of xanthan of Composition P. This formulation provided acomposition that could be evenly coated. Compositions P-Q demonstratethe importance of proper formulation on the ability of the film matrixto conform to a particular coating technique.

The films produced from Composition S contained a large amount of air inthe films. This is shown by the dried film thickness which was the samedespite that variation in the coated thickness as in Table 7.Microscopic examination of the film revealed a large number of airbubbles in the film. In order to correct for the addition of air in thefilms, care must be taken in the mixing process to avoid air inclusion.

Composition T included a change in the solvent to 60/40 water ethanol.Composition T was stirred slowly for 45 min. to deaerate the mixture.The dried weight film products T1 and T2 was consistent with theincrease in solids from T1 to T2. The films dried much faster with lessthan 5% moisture. With the particular combination of ingredients inComposition T, the substitution of part ethanol for part water allowedthe film to dry more quickly. The elimination of air from the film as aresult of the slow stirring also contributed to the uniformity of thefinal film product and the faster drying time.

Only water was used as a solvent in Composition U. The dried weight ofthe U1-U3 changed consistently in accordance with the change in coatingthickness indicating that no air bubbles were present. However, thesefilms contained 20% moisture upon exit from the oven, unlike the filmsof Composition T, which included part ethanol and dried completely.

The amount of solids was increased and the amount of water was decreasedin Compositions V1 and V2. The dried weight was greater than U1-U3 dueto the increase in solids, however the films still contained 20%moisture upon exit from the oven, similar to Composition U.

The coating line speed was reduced for Composition V3, to preventpremature drying of the exposed top film surface. This film productdried to 6% moisture.

While increasing the amount of solids improved the film weight, longerdrying times were required. This was due to the surface of the filmsealing preventing easy removal of the water. Therefore, forCompositions W1-W3, the temperature in the first 3 m section of thedryer was decreased. This prevented the premature drying of the topsurface of the films. Even at greater film thicknesses, the films weredried to 5% moisture even at faster coater line speeds.

TABLE 8 Weight (g) Ingredient X Y Z AA Loratadine 104.69 Zomig 52.35Paxil 104.69 Hydroxypropyl 320 320 320 150 methylcellulose Sweetenerblend 60 60 60 0.4 Dimethicone 1.5 1.5 1.5 1.5 Propylene glycol 100 100100 Water 1440 1440 1440 790 Cream essence 0.4 Polyvinyl pyrrolidinone 4Ethanol 40 Cocoa 55.2 Polyoxy1-40-stearate 7

Compositions X, Y and Z of Table 8 were taste mask coated using a Glattcoater and Eudragit E-100 polymethacrylate polymer as the coating. Thecoating was spray coated at a 20% level. Therefore 10 mg of drug 12.5 mgof the final dry product must be weighed.

The base formula which excluded the drug additive was mixed with care tonot incorporate air. After initial mixing the formula was slowly mixedto deaerate over 30 min. During this time the drug was weighed andprepared for addition to the base mix.

For Composition X, the Loratadine (80% drug) was added slowly to the mixwith stirring. After 5 min. of stirring, the total mix was added to thepan of a three roll coater set (reverse roll coater) at 30 microncoating thickness.

The process bottom temperature was set at 90° C. with no top heat orair, the bottom air velocity was set at 40 m/sec., and the line speedwas set at 1.3 m/min. Total drying time for the film was 4.6 min.

The liquid was coated at 30 microns and dried in the oven in less than 5min. The film was flexible and a 1″×0.75″ piece weighed 70 mg andcontained 10 mg of Loratadine.

The experiment was repeated for Compositions Y and Z, Zomig and Paxil,respectively. Both produced flexible films with the target weight of 70mg containing 5 mg of Zomig and 70 mg containing 10 mg of Paxil,respectively.

The products were sweet without any noticeable drug aftertaste.

The ingredients of Composition AA were mixed in order to reduce aircaptured in the fluid matrix. After mixing 45 g of loratadine coated ata 80% active level and 20% coating using Eudragit E-100, this mixturewas added slowing with mixing until the drug was evenly dispersed,approximately 5 min. The liquid was then deposited into the 3 rollcoater (reverse roll coater) and coated at 30 microns at a line speed of1.3 m/min. The oven temperature was set at 90° C. to apply air and heatto the bottom only, with an air velocity set at 40 m/sec. The dried filmwas 0.005 inch. thick (5 mil) and was cut into 1 in.×0.75 in. piecesweighing 70 mg +/−0.7 mg, demonstrating the uniformity of thecomposition of the film. The film was flexible with 5% moisture, free ofair bubbles, and had uniform drug distribution as seen under the lightmicroscope, as well as shown by the substantially identical weightmeasurements of the film pieces.

While there have been described what are presently believed to be thepreferred embodiments of the invention, those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended toinclude all such changes and modifications as fall within the true scopeof the invention.

What is claimed is:
 1. A process for making a film dosage unit having asubstantially uniform distribution of components, comprising the stepsof: (a) providing at least one predetermined well which corresponds toan individual film dosage unit; (b) combining and mixing a polymercomponent and solvent to form a matrix with a uniform distribution ofthe components; (c) casting the matrix onto the at least onepredetermined well; and (d) drying the matrix through application ofheat to form at least one film dosage unit defined by the predeterminedwell.
 2. The process of claim 1, wherein the predetermined well has abottom side and the step of drying the matrix comprises applying heat tothe bottom side of the predetermined well.
 3. The process of claim 1,further comprising the step of adding an active component to the matrixof step (b).
 4. The process of claim 1, wherein the matrix has aviscosity of at least about 400 cps.
 5. The process of claim 1, whereinthe film dosage unit is ingestible.
 6. The process of claim 1, whereinthe film dosage unit is flexible when dried.
 7. The process of claim 1,wherein the film dosage unit is self-supporting.
 8. The process of claim3, wherein uniform distribution determines the amount of activecomponent per area.
 9. The process of claim 1, wherein the solvent is acombination of water and a polar organic solvent.
 10. The process ofclaim 1, wherein the solvent is water.
 11. The process of claim 1,wherein the solvent added in step (b) has a weight percent of at leastabout 30%.
 12. The process of claim 3, wherein the active component is amember selected from the group consisting of medicaments, flavors,fragrances, enzymes, preservatives, sweetening agents, colorants,spices, vitamins, and combinations thereof.
 13. The process of claim 1,wherein the polymer component is a member selected from the groupconsisting of water soluble polymers, water insoluble polymers andcombinations thereof.
 14. The process of claim 1, wherein the polymercomponent is a cellulose derivative.
 15. The process of claim 13,wherein the water soluble polymer is a member selected from the groupconsisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose,polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum,tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl copolymers, starch andcombinations thereof.
 16. The process of claim 3, wherein each of thedosage units contains a substantially equal amount of the activecomponent.
 17. A method of administering an accurately dosed filmproduct, comprising the steps of: (a) preparing a film dosage unit bythe steps of: (i) providing at least one predetermined well whichcorresponds to an individual film dosage unit; (ii) combining and mixinga polymer component, a solvent and an active component to form a matrixwith a uniform distribution of the components; (iii) casting the matrixonto the at least one predetermined well; and (iv) drying the matrixthrough application of heat to form at least one film dosage unitdefined by the predetermined well; (b) removing the film dosage unitfrom the predetermined well; and (c) applying the film dosage unit tothe oral cavity of a mammal.
 18. A film dosage unit in a predeterminedwell container comprising: (a) a predetermined well; and (b) a filmdosage unit contained in said well, wherein said film dosage unit isformed by the steps of: (i) combining and mixing a polymer component, asolvent and an active component to form a matrix with a uniformdistribution of said components; (ii) casting said matrix onto saidpredetermined well; and (iii) drying said matrix through application ofheat to form at least one film dosage unit defined by said predeterminedwell.